NPY1R Antagonist
BIBO3304
BIBO3304 is a potent and selective NPY receptor Y1 antagonist. An (R)-argininamide derivative, it shows subnanomolar affinity for the human and rat Y1 receptor while displaying very low affinity for Y2, Y4 and Y5 receptors. In rodents, it has inhibited food intake induced by fasting or application of NPY. Its distomer, BIBO3457, is available as negative control.
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Neuropeptide Y (NPY) is a 36 amino acid polypeptide that is abundantly expressed both in the peripheral and central nervous system, including the hypothalamus1. It is an endocrine and neuronal messenger that has been implied in the regulation of several physiological functions such as food intake and elevation of blood pressure2-4. The NPY-Y receptor system consists of three peptide ligands (NPY, pancreatic polypeptide and peptide YY) that interact in mammals with up to four receptors (Y1, Y2, Y4 and Y5) with different selectivity and affinity. These receptors are part of the G-protein coupled receptor superfamily that are coupled to the intracellular Ca2+ release and the inhibition of cAMP synthesis5.
Research on the NPY receptors showed that the Y1 receptor could influence food intake6.
Several small-molecule compounds and peptides have been characterised as NPY-Y1 antagonists with possible applications in tumor treatment, obesity, and bone loss3,7-9. Reported crystal structures of human NPY-Y1 receptor interacting with selective antagonists enable structure-based drug discovery10. Next to achieving sufficient potency, NPY-Y1 antagonists often struggle with selectivity, poor bioavailability, or brain penetration.
Crystal structures of NPY-Y1 complex with literature compound MK299 showing the location of the binding site10
BIBO3304 displays an IC50 < 1nM for both the human and the rat Y1 receptor in cells stably transfected with the human/rat Y1 receptor (SK-N-MC cells).9 BIBO3304 binds with more than 1,000-10,000-fold lower affinity to the other subtypes (Y2, Y4 and Y5). Its (S)-enantiomer BIBO3457 exhibits an IC50 > 10,000 nM for the human and an IC50 > 1,000 nM for the rat Y1 receptor.9
| Probe name / negative control | BIBO3304 | BIBO3457 |
| MW [Da]a | 529.6 | 529.6 |
| Human Y1/BHK (IC50) [nM] | 0.7 | > 10,000 |
| Human Y1/SK-N-MC (IC50) [nM] | 0.4 | 1,300 |
| Rat Y1/293 (IC50) [nM] | 0.7 | > 1,000 |
| Human Y2/SMS-KAN (IC50) [nM] | > 10,000 | > 10,000 |
| Human Y2/BHK (IC50) [nM] | > 1,000 | > 10,000 |
| Rat hippocampus (Y2)/CHO (IC50) [nM] | > 10,000 | n.a. |
| Human Y4/CHO (IC50) [nM] | 12,300 | 24,000 |
| Rat Y4/CHO (IC50) [nM] | > 10,000 | > 10,000 |
| Human Y5/293 (IC50) [nM] | > 10,000 | 28,000 |
| Rat Y5/CHO (IC50) [nM] | 21,000 | 23,000 |
aFor the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
| Probe name / negative control | BIBO3304 | BIBO3457 |
| logD @ pH 2 / pH 11 | 0.9 / >6.0 | 0.7 / 1.8 |
| Solubility @ pH 6 [µg/mL] | 374 | 96 |
| Caco-2 permeability AB @pH7.4 [*10-6 cm/s] | 0.1 | 0.1 |
| Caco-2 efflux ratio | 3 | 2 |
| MDCK permeability PappAB @ 1µM [10-6 cm/s] | 0.6 | 0.5 |
| MDCK efflux ratio | 0.7 | 0.6 |
| Microsomal stability (human/mouse/rat) [% QH] | 45 / <23 / 81 | 35 / 34 / 78 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 4 / 15 / 33 | >4 / 37 / 31 |
| Plasma Protein Binding (human/mouse/rat) [%] | 90 / 91 / 84 | 75 / 90 / 84 |
| hERG [inh. % @ 10 µM] | 5 | 10 |
| CYP 3A4 (IC50) [µM] | >50 | >50 |
| CYP 2C8 (IC50) [µM] | >50 | 31 |
| CYP 2C9 (IC50) [µM] | >50 | >50 |
| CYP 2C19 (IC50) [µM] | n.a. | >50 |
| CYP 2D6 (IC50) [µM] | >50 | >50 |
BIBO3304 is able to reduce food intake of rats that were stimulated either by endogenous (induced by fasting) or by exogenous NPY application9. The negative control BIBO3457 shows no significant influence on food intake in rats that were stimulated by exogenous NPY application9.
(a) Inhibition of NPY (1 µg, n = 25) induced feeding by BIBO3304 in adult male Chbb:Thom rats. (b) Lack of the effect of the inactive enantiomer BIBO3457 to inhibit NPY induced feeding (n = 8)9.
Effect of 30 µg of BIBO3304 (15 µg, bilateral) on food in 24 h fasted rats (n = 12)9.
BIBO3457 is the distomer of the active NPY-Y1 receptor antagonist BIBO3304. It displays low affinity towards both the human and the rat Y1 receptor9.
BIBO3457, which serves as a negative control
BIBO3304 was tested on 146 targets in a selectivity panel and showed ≥1,000-fold selectivity for 148 targets (≤50% inhibition @ 10 µM). In three assays (D2S(h), kappa KOP (h) and V1a (h)), the compound showed inhibition between 60-71%.
The negative control BIBO3457 showed more than 50% inhibition @ 10 µM in 6 out of 44 targets.
| SELECTIVITY DATA AVAILABLE | BIBO3304 | BIBO3457 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BIBO3457_selectivityData.xlsx
BIBO3304_selectivityData.xlsx
BIBO3304 is a potent and selective in vitro and in vivo tool compound. It acts as an antagonist on the neuropeptide Y (NPY) receptor Y1. Its distomer BIBO3457 is available as negative control. BIBO3304 successfully demonstrated in a rodent assay that it could significantly inhibit food intake induced by fasting or application of NPY. It is our second NPY receptor antagonist, after our NPY2R antagonist launched in December, 2020.
Effects of neuropeptide Y on the cardiovascular system Trends
Edvinsson L., Håkanson R., Wahlestedt C., Uddman R.
Pharmacol. Sci. 1987, 8, 231-235.
Structure-Activity Relationships of Nonpeptide Neuropeptide Y Receptor Antagonists
Brennauer A., Dove S., Buschauer A.
Handbook of Experimental Pharmacology 2004, 162.
Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor
Yang Z., Han S., Keller M., Kaiser A., Bender B. J., Bosse M., Burkert K., Kögler L. M., Wifling D., Bernhardt G., Plank N., Littmann T., Schmidt P., Yi C., Li B., Ye S., Zhang R., Xu B., Larhammar D., Stevens R. C., Huster D., Meiler J., Zhao Q., Beck-Sickinger A. G., Buschauer A., Wu B.
Nature 2018, 556, 520-524.
When you plan a publication, please use the following acknowledgement:
BIBO3304 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.